Without tight regulatory mechanisms, this could dramatically alte

Without tight regulatory mechanisms, this could dramatically alter the IOX1 molecular weight neuronal membrane potential, leading to neuronal hyperexcitability and seriously compromising CNS

function.32 Such a scenario is prevented by the buffering of extracellular K+ by glial cells33,34 (Figure 2, orange box). Indeed, astrocytes have a strongly negative resting potential and express a number of potassium channels, resulting Inhibitors,research,lifescience,medical in a high membrane permeability to K+.35 These features, in conjunction with the action of the Na+/K+ ATPase, enable astrocytes to accumulate the excess extracellular K+ 36, which can then travel in the astrocytic syncitium through gap junctions down its concentration gradient.34,35 Inhibitors,research,lifescience,medical This allows for the spatial dispersion of K+ from areas of high concentration to areas of lower concentration where it can be extruded either into the extracellular space or the circulation, thus

maintaining the overall extracellular K+ concentration within the physiological range. In addition to spatial buffering, other mechanisms such as the transient storage of K+ ions appear to contribute to the potassium-buffering capacity of astrocytes.32 Supply of energy substrates Although the brain represents only 2% of the body weight, it is responsible for the consumption of an estimated 25% of all glucose in the body.37 This disproportionate energy need Inhibitors,research,lifescience,medical compared with other organs can be largely explained by the energetic cost of maintaining the steep ion gradients necessary for the transmission of action potentials.38 For this reason, neurons in particular have very high energy requirements, and are therefore highly dependent upon Inhibitors,research,lifescience,medical a tight regulation of energy substrate supply in order to sustain their normal function and cellular integrity. As mentioned previously, the morphological features of astrocytes ideally position them to sense neuronal activity at the synapse and respond with the appropriate metabolic supply via their astrocytic endfeet which almost entirely enwrap the intracerebral blood Inhibitors,research,lifescience,medical vessels (Figure 3). In line with this, an

increasing body of evidence suggests that astrocytes play a key role in the spatiotemporal coupling between neuronal activity and cerebral blood flow (known as functional hyperemia) in a process that involves transient neurotransmitterinduced increases of [Ca2+]i in astrocytes, the subsequent propagation TCL of Ca2+ waves through the astrocytic syncitium and the release of vasoactive substances (such as arachidonic acid metabolites or ATP) by astrocytic endfeet.13 Importantly, the role of astrocytes in functional hyperemia does not preclude a concerted contribution of neurons via the release of vasoactive substances such as neurotransmitters, nitric oxide, H+, and K+ to name a few.39 Figure 3. Astrocytic endfeet in humans.

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